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Cystic Fibrosis Scientists Discover Abnormal Response to Lung Infections

Date: 
Thursday, October 5, 2017

The inability to clear bacteria from the lungs is the result of a lack of healthy mucus secreted in the airways of those with cystic fibrosis, according to research published today in the prestigious Nature Communications journal.

 “For a very long time, there has been discussion about whether cystic fibrosis was a bacteria-infection problem, an inflammation problem, or an immune system problem,” says Juan Ianowski, the lead author of the paper.

Xiaojie "Jay" Luan, PhD student, and Juan  Ianowski prepare
the sample stage at the  BMIT beamline.

Ianowski, associate professor in the Department of Physiology at the University of Saskatchewan, and a team of 18 researchers have concluded that the genetic mutation that causes cystic fibrosis prevents normal secretion of airway surface liquid including mucus. Using a new imaging technique they developed at the Canadian Light Source, they determined that the production of airway surface liquid in response to bacteria is abnormal, and might lead to a cascade of infection and inflammation in lungs as the incurable disease progresses.

“Most patients are born with healthy lungs and as time passes, they start developing infections and inflammation. The infections are cleared and a new one occurs, and then there is an infection and it’s cleared and a new one occurs. Eventually, the infections are permanent and the bacteria never leave the lungs,” says Ianowski.

Cystic Fibrosis Canada estimates that one in every 3,600 children born in Canada has cystic fibrosis. It is the most common fatal genetic disease affecting Canadian children and young adults, according to the organization’s website.

People with healthy lungs inhale between 5,000 and 14,000 germs every day. These germs are caught in their airways by a sticky mucus with antimicrobial properties that kills the germs. Tiny hairs called cilia then push the germs out of the respiratory tract and the body clears the mucus and the germs.

The hypothesis that people with cystic fibrosis do not have normal production of mucus in response to inhalation of pathogens was developed decades ago, but until now, there was no way to test it.

Ianowski and his team spent seven years developing the synchrotron-based method needed to analyze the production of mucus in a living animal. The normal layer of mucus is as thin as 80 microns. That’s thinner than a strand of hair.

At the Canadian Light Source, they imaged the normal lungs of pigs focusing on the liquid layer, measuring it and analyzing its production.  They also were able to image how the liquid in the airway reacts when bacteria are introduced. Then, they repeated the process with pigs who modeled cystic fibrosis.

“We discovered and showed for the first time ever that the normal airway response to inhalation of pathogens is producing liquid. This is a process that depends on CFTR (cystic fibrosis transmembrane conductance regulator) expression. So if you don’t have normal CFTR, it doesn’t work. In CF pigs, this response is absent,” explains Ianowski.

Dr. Julian Tam and Juan Ianowski at the BMIT beamline.

Dr. Julian Tam, a respirologist in the Department of Medicine at the U of S and director of the Saskatoon Adult Cystic Fibrosis Clinic, collaborates with Ianowski on cystic fibrosis research in association with the Respiratory Research Centre at the U of S and was a member of the research team.

He calls the research findings “exciting” because they provide more insight into what is actually happening in the lungs at a microscopic level.

“Having a better understanding of the pathway that can cause lung disease could eventually pave the way for novel treatment strategies.” says Tam.

What the research suggests to physicians and patients is that the current medical practice of aggressive antibiotic treatments for patients with CF is a sound practice.

Ianowski says this research could only have been conducted at the Canadian Light Source BMIT beamline and the University of Saskatchewan. No other synchrotron in the world has the capacity to accommodate the research involving large live animals over several days. The team in Saskatoon included veterinarians and vet technicians from the Western College of Veterinary Medicine, synchrotron scientists from BMIT, as well as undergraduate and graduate students from the Department of Physiology.

“We are able to exploit the amazing expertise available here. The vet team is outstanding. The know-how for doing research involving pigs is incredible,” says Ianowski.

Ianowski and his team continue to research cystic fibrosis and how it affects lungs. They are exploring the role of bacteria in triggering infections as well as the response of lungs to the inhalation of hypertonic saline. Their research is financed, in part, by Cystic Fibrosis Canada.

Luan, Xiaojie, George Belev, Julian S. Tam, Santosh Jagadeeshan, Noman Hassan, Paula Gioino, Nikolay Grishchenko, et al. “Cystic fibrosis swine fail to secrete airway surface liquid in response to inhalation of pathogens.” Nature Communications 8, 786 (2017). DOI: 10.1038/s41467-017-00835-7

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